ABSTRACT Cardiovascular disease (CVD) risk factors disproportionately affect black adults, and these disparities are evident early in the life course. Genetic factors do not appear to explain this difference, and studies have increasingly implicated socioeconomic risk factors. Among the most prominent risk factors for racial disparities in CVD is educational attainment, which is strongly correlated with smoking, hypertension, and CVD over the life course. Yet it is unclear which aspects of schooling are most salient. One possible explanation for racial disparities in CVD is that black youth often attend highly racially segregated schools. Segregation is thought to be linked with CVD due to increased stress and discrimination; social norms and peer influence; and the constraining of socioeconomic opportunities that reduces income and healthcare access later in life. Yet despite the fact that school segregation has increased in recent years, there are no studies examining the effects of recent school segregation trends on CVD risk factors. The goal of this study is to provide this urgently needed evidence. In particular, we take advantage of a unique natural experiment, overcoming methodological challenges in the previous literature on the effects of education on CVD. Since 1990, numerous local court decisions have resulted in ?resegregation? in school districts across the country. We link nationwide data on these court decisions and school district-level measures of school segregation with CVD outcome data from two large nationally representative U.S. cohort studies of affected youth: the National Longitudinal Study of Adolescent to Adult Health (Add Health, N?90,000) and the Panel Study of Income Dynamics (N?8,000). We employ the quasi-experimental technique of instrumental variables analysis, which reduces typical confounding by factors such as unobserved individual and family characteristics. In Aim 1, our goal is to estimate the short- term effects of school segregation on CVD risk factors?including smoking, physical activity, obesity, and mental health?among youth while they are still in school. In Aim 2, we will examine the long-term effects of school segregation in the decades that follow, with outcomes including those in Aim 1 in addition to objectively measured CVD biomarkers, diabetes, and hypertension. We will also undertake exploratory analyses to determine possible mediating pathways. In Aim 3, we will identify vulnerable subgroups whose development of CVD risk factors differs in response to school racial segregation. This will enable future interventions to be tailored to the most vulnerable individuals. We will employ both hypothesis-driven and hypothesis-generating statistical techniques, including innovative machine learning methods that allow for more complex and robust subgroup identification. Overall, the expected outcome of this research is to produce rigorous evidence on the effects of school racial segregation on CVD risk factors, helping to inform school-based, clinical, and community interventions to reduce persistent and inequitable racial disparities in CVD.